Indenyl acids and derivatives thereof



3,312,730 INDENYL ACIDS AND DERIVATIVES THEREOF Charles A. Winter, Box143, Blue Bell, Pa. 19422, and ggggg-Ying Shen, 728 Tamaques Way,Westfield, NJ.

No Drawing. Original application May 6, 1963, Ser. No. 278,390. Dividedand this application Sept. 14, 1965, Ser. No. 498,181

Claims. (Cl. 260-473) This application is a division of our copendingapplication Ser. No. 278,390, filed May 6, 1963.

This invention relates to a new method of treating inflammation and to apreferred class of new compounds of the indene series for suchtreatment. More specifically, it relates to the treatment ofinflammation with ez-(laralkylidene or heteroaralkylidene-3-indenyl)lower aliphatic acids and their salts, amides and esters. Morespecifically also, it relates to the treatment of inflammation withcompounds of the formula:

CCO-M R5 I i/ in which R, may be aryl or heteroaryl;

R may be hydrogen, alkyl, aralkyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkyl, alkylthio and arylthio;

R may be hydrogen, lower alkyl, halogeno lower alkyl,

fluorine, amino, acylamino, dialkylamino, N-morpholino, alkenyl,aralkyl-thio, hydroxy and alkoxy and together with R, a methylene;

R is hydrogen or together with R, a methylene;

R R and R each may be hydrogen, alkyl, alkoxy,

nitro, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl,sulfamyl, alkylthio, mereapto, alkylsulfonyl, arylsulfonyl, halogen,cyano, carboxyl, carbalkoXy, carbamido, aryl, halogenoalkyl, alkenyloxy,aralkyloxy, alkenyl, aryloxy, cycloalkyl and cycloalkyloxy, and

M may be hydroxy, lower alkoxy, substituted lower alkoxy, amino,alkylamino, dialkylamino, N-morpholino, hydroxyalkylarnino,polyhydroxyalkylamino, di-

alkylaminoalkylarnino, aminoalkylamino, and the group OMe in which Me isa cation as well as the 2,3-dihydro derivatives of said compounds.

More specifically, also, in a separate and distinct aspect, thisinvention relates to a preferred new class of compounds especiallyuseful as antiinflammatory agents, having the formula:

in which R is aryl or heteroaryl, having at least one 3,312,730 PatentedApr. 4, 1967 R is hydrogen or together with R, a methylene;

R is alkyl, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino,dialkylaminoalkyl, sulfamyl, alkylthio, mercapto, alkylsulfonyl,arylsulfonyl, halogen, cyano, carboxyl, carbal-koxy, carbamido, aryl,halogenoalkyl, alkenyloxy, aralkyloxy, alkenyl, aryloxy, cycloalkyl andcycloalkyloxy;

R and R are hydrogen or any of the groups defining R and M is hydroxy,lower alkoxy, substituted lower alkoxy,

amino, alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino,polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino, and thegroup OMe, in which Me is a cation;

as well as the 2,3-dihydro derivatives of said compounds. The compoundsof the above description, especially those of the preferred class inwhich the aryl or heteroaryl group represented by R has at least onefunctional substituent and in which both R and R are other thanhydrogen, possess a high degree of anti-inflammatory activity. They arehighly active and are of value in the treatment of arthritic anddermatological disorders and like conditions responsive toanti-inflammatory drugs. They also possess a useful degree ofanti-pyretic activity. More important, these compounds possess thesebeneficial activities with only a small fraction of the ulcerogenic sideeffect which is so characteristic of most anti-inflammatory drugs. Theulcerogenic effect is found in these compounds to be greatly reduced andin many cases just about completely eliminated. These compounds can beadministered orally in capsules or may be applied topically orintravenously. The dosage in each case will depend on the specificcompound and the type and severity of the infection. For the presentcompounds, dosages of the order of 10 to 2000 mg. per day may be usedfor arthritic conditions, depending on the activity of the compound andthe reaction sensitivity of the patient.

The compounds used in the method of our invention are a-(l-aralkylideneor heteroaralkylidene-3-idenyl) aliphatic acids. Especially, they arecompounds of the formula given above. The substituents on the 1-positionare aralkylidene or heteroaralkylidene groups derived from aromatic orheterocyclic aromatic aldehydes. In the preferred class of compoundswhich form a separate aspect of this invention, these aldehyde carry atleast one functional substituent, preferably in the para position. Theterm functional substituent means one other than hydrogen or alkyl,i.e., one whose polariy and general character affects the electrondistribution in the aryl or heteroaryl group, causing activation of somepositions and/or inactivation of others. On the 2-position of the indenenucleus, one can place a number of substituents such as alkyl, aralkyl,aryl, alkoxy, arylthio, nitro, amino, dialkylamino, etc. or the2-position may be unsubstituted,

\ in which case R becomes hydrogen. In the preferred class, which formsa separate aspect of the invention, R must be other than hydrogen.

Since these compounds are 3-indenyl aliphatic acids, the 3-position musthave an aliphatic acid side chain 7 with the indenyl nucleus on thealpha carbon of the aliphatic acid. Normally, one has an acetic orpropionic acid side chain, but other lower aliphatic acid side chainssuch as y3,p,fl-trifluoro-u-indenyl propionic acids, alkenoic acids andhigher alkanoic acids as well as other aliphatic acids such ascyclopropane carboxylic acids can be equally well used. In addition,contemplated within the scope of this invention are 3-indenyl glycinesand N-alkyl-S-indenylglycines. In such compounds the acetic acid sidechain carries in the a-position an amino or dialkylamino group. They areprepared by the reaction of hydroxylamine on the corresponding3-indenylglyoxylate (from the 3-unsuba) stituted indene and oxalylchloride followed by esterification) and reduction of the oxime. Theunsubstituted aamino group may be alkylated by any good alkylatingagent, such as dialkyl sulfate or alkyl halides.

The benzene ring of the indene nucleus may carry from one to threesubstituents of a number of types, preferably alkyl, alkoxy, nitrogenand sulfur derivatives or Various carboxylic acid functional derivativesas enumerated above and described further below. In the case of thepreferred compounds which form a separate aspect of this invention,there must be such a substituent. Preperably, the -position of theindene should be substituted. Not only the free acids, but the esters,amides and salts are included within the scope of this invention.

In the preparation of the compounds used in the method of thisinvention, the starting material is a ,B-aryl propionic acid. This isprepared according to the scheme shown in Flow Sheet I. Note that R Rand R in this Flow Sheet do not have as extensive a definition as in athe definition of the compounds included in our invention.

The reason for this is that it is very easy to make a large numberof'these other substituted indenes from the nitro iudenes. In thepreparation described in Flow Sheet I, several alternative routes can beused. Thus, a substituted benzaldehyde may be condensed with asubstituted acetic ester in a Claisen reaction or with an a-halogenopropionic ester in a Reformatsky Reaction. The resulting unsaturatedester is reduced and hydrolyzed to give the benzyl propionic acidstarting material. Alternatively, a substituted malonic ester in atypical malonic ester synthesis and acid hydrolysis of the resultingsubstituted ester yields the benzyl propionic acid directly. This lattermethod is especially preferable for nitro and alkylthio substituents onthe benzene ring.

Equivalents:

X =halogen, usually Cl or B1". 7

E=esterifying group, usually methyl, ethyl or benzyl.

R =H, alkyl, halogenated alkyl, aralkyl, aryl and heteroaryl. 7

R R and R =H, alkyl, alkoxy, nitro, alkylthio, alkylsulfonyl,arylsulfonyl, halogenoalkyl, etc. as defined on Page 1, at least one notbeing H.

Reagents:

@ Zn dust in anhydrous inert solvent such as benzene and ether.

@ KHSO or p-toluene sulfonic acid.

@ NaOC H in anhydrous ethanol at room temperature.

@ H palladium on charcoal, 40 p.s.i. room temperature.

@NaOH in aqueous alcohol at 20-100".

@ NaOC H or any other strong base such as NaH or K-t-butoxide. Acid.

(I) Preparation of fi-arylpropionic acid starting RB VIII VIIEquivalents:

X, E, R R R same as Flow Sheet I.

R =I-I, lower alkyl, halogenated lower alkyl.

R =aryl or heteroaryl.

Reagents:

(D Friedel-Crafts Reaction using a Lewis Acid catalyst Cf. OrganicReactions, Vol. II, p. 130.

'@ Heat with polyphosphoric acid,

-@ Reformatsky Reaction: Zn in inert solvent, heat.

(4) p-Toluene sulfonic acid and CaCl or I at 200.

@ Wittig Reaction using (C H P==C-COOE 20- in ether or benzene.

@ Reaction with aldehyde or ketone, using strong base as' catalyst(K-t-butoxide or any alkoxide, NaOH, KOH, NaNH etc.), warming ifnecessary to form the carbanion in solvents such as liquid ammonia,dimethylformamide, 1,2 dimethoxyethane, pyridine, and aqueous alcohol.

@ Bromine, 0 carbon tetrachloride and then collidine, -175".

(5}) 20-80". R CH=P(Ph) ether or benzene as solvent.

(II) Preparation of a-(1-substituted-methylenyl-3- indenyDaIip/zaticacids r OHzCH-COOH XI XIII Ills OH-C O O E x/ XIV Ha I

' clacoon -CH c uzrooon XVII In the preparation of the compounds used inthis invention, again a number of routes are possible, as shown in FlowSheet II. The first step is the ring closure of the fi-aryl propionicacid to form an indanone which may be carried out by a Friedel-CraftsReaction using a Lewis acid catalyst (Cf. Organic Reactions, Vol. 2, p.130) or by heating with polyphosphoric acid. The indanone may becondensed with an ot-halo ester in the Reformatsky Reaction to introducethe aliphatic acid side chain by replacing the carboxyl group.Alternatively, this introduction can be carried out by the use of aWittig Reaction in which the reagent is a a-triphenylphosphinyl ester, areagent which replaces the carbonyl with a double bond to a carbon. Thisis then immediately rearranged into the indene. If the ReformatskyReaction route is used, the intermediate 3-hydroxy-3-aliphatic acidderivative must be dehydrated to the indene. The introduction of thel-substituent is carried out again in one of two ways. The first is thedirect reaction of the indene with the aldehyde of the structuralcharacteristics defined, using a strong base as a catalyst and warming,if necessary, to form the carbanion. A variety of other bases such assodium hydroxide, potassium hydroxide, sodamide, quaternary ammoniumhydroxides and the like may be used, The reaction can be carried out ina number of solvents such as polar solvents like dimethoxyethane,aqueous methanol, pyridine, liquid ammonia, dimethylformamide and thelike or even in non-polar solvents such as benzene, etc. Alternatively,an indanone can be brominated and then dehydrogenbrominated to anindenone as described by H. 0. House et al. in J. Am. Chem. Soc. 82,1452 (1960), and the indenone carbonyl replaced by the substituent usingthe u-triphenyl-phosphinyl compounds of the desired structure. Thesereactions are all described in Flow Sheet II. Note that E in the thirdstage and in the 5th stage is a lower alkoxy group and thus forms alower alkyl ester of the desired compound. This can then be hydrolyzedto give the free acids from which the salts, other esters and the amidesmay be formed. Steps 6, 7 and 8 of Flow Sheet II can also be carried outwhen E is hydrogen.

In the introduction of the l-substituent by either of the methodsdescribed in Flow Sheet II, any aryl or heteroaryl aldehyde may be usedeither directly in the base condensation or in the form of its Wittigreagent in the alternative route. Among the aldehydes which may be usedare benzaldehyde and substituted benzaldehydes such as4-chlorobenzaldehyde, 2-chlorobenzaldehyde, 4-brom'obenzaldehyde,2,4-dichloro or dibromobenzaldehyde, 4-methylthiobenzaldehyde, 4-methyl,ethyl, propyl, i-propyl, butyl or t-butylbenzaldehyde,4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde,3-trifluoromethylbenzaldehyde, 4-dimethylsulfamylbenzaldehyde,4-methylsulfamylbenzaldehyde, 2-nitro-4-chlorobenzaldehyde,2-methoxy-4-dichlorobenzaldehyde, Z-nitro-4-methylbenzaldehyde,2-nitr0-4-fiuorobenzaldehyde, 2-nitro-4-methoxybenzaldehyde,p-anisaldehyde, salicylaldehyde, vanillin, p-terephthalaldehydic acidamides (e.g.,

the methyl, dimethyl, methylethyl and diethylamides) pyridine 2,3 and4-aldehydes, thiophene 2 or 3-aldehydes, pyrazine aldehyde,pyrr'ol-2-aldehyde, furfural, pyrimidine-Z-aldehyde, a and13-naphthaldehyde, benzothiazole-Z-aldehyde,3-nitrothiophene-Z-aldehyde, furyl-Z-aldehyde,1-methylpyrrol-2-aldehyde, thiazole-Z-aldehyde,1-methylpyrazole-5-aldehyde, oxazole-4-aldehyde,5-styryl-6-ethoxyoxazole-Z-aldehyde, 1-methylpyridine-4-aldehyde,2-ethoxypyrane-3-aldehyde, 1-phenylpyridazine-6-a1dehyde,l-methylindole-3-aldehyde, 5-chl'orobenzo-3-aldehyde,thionaphthene-3-aldehyde, benzofuran-S-aldehyde,1-methylbenzimidazole-Z-aldehyde, 7-aza-indole-3-aldehyde,3-methylbenzopyrane, quinoline and S-aldehydes,

7 I isoquinoline-4-aldehyde, quinoxaline-Z-aldehyde,naphthyridine-2-aldehyde, benzoxazole-Z-aldehyde,

and the like. Substituents on the aromatic rings are preferably in the4-positi'on.

Although the syntheses described produces esters of the acids of thisinvention, some desired esters are more easily obtained by forming asimple ester of the final acid, hydrolyzing to the free acid andre-esterifying. The simple lower alkyl or benzyl esters are usually theones used in the synthesis of the compounds. Other esters are moredesirable from the standpoint of therapeutic utility of the compounds,such as the methoxymethyl, diethylaminoethyl, dimethylaminoethyl,dimethylaminopropyl, diethylaminopropyl, N-pyrollidinylethyl,N-piperidinylethyl, N-pyrollidinylmethyl, N-methyl-2-pyrollidinylmethyl,N-morpholinylethyl, N-ethy1-2-piperidinylethyl, 4-methyl-l-piperazinylethyl, methoxyethoxyethyl, and the like. These aremostly prepared from the corresponding alcohol and the indenyl acid.

The amides, both the simple amide and the substituted amides, aresimilarly prepared from the indenyl acids and the corresponding amines.Especially useful therapeutically are the morpholide, thebishydroxyethylamide and the like.

Similarly, salts are obtained by neutralizing the indenyl acids withbases or by metathesis of other salts. Especially useful are themetallic salts such as the alkali metal or alkaline earth salts and theamine and quaternary ammonium salts, which are water soluble, but theheavy metal salts such as iron, aluminum, etc. are also usable for somepurposes.

As has been pointed out above, it is preferable in the preparation ofmany types of the compounds of this invention, to use a nitrosubstituent on the benzene ring of the indanone nucleus and covert itlater to a desired sub stituent since by this route a great manysubstituents can be reached. This is done by reduction of the nitro tothe amino group followed by use of the Sandmeyer Reaction to introducechlorine, bromine, cyano or xanthate in place of theamino. From thecyano derivatives hydrolysis yields the carboxamide and carboxylic acid;other derivatives of the carboxy group such as the esters can then beprepared. The xanthates, by hydrolysis, yield the mercapto group whichmay be oxidized readily to the sulfonic acid or alkylated' to analkylthio group which can then be oxidized to alkylsulfonyl groups.These reactions may be carried out either before or after theintroduction of the l-substituent.

The procedure of Flow Sheet II is especially advantageous whensubs-tituents other than alkyl groups are to be on the 2-position of theindene ring system. Such substituents as phenyl, benzyl, alkoxy,arylthio such as phenylthio, alkylthio such as methylthio and ethylthioand nitro are best introduced by constructing the proper indanone andreplacing the keto group by the desired aliphatic acid side chain.

Many of the indanones usable in Flow Sheet 11 are known in theliterature and are thus readily available as intermediates for the restof the synthesis. Among the compounds of this type which are known are:

5 -methoxyindanone 6-methoxyindanone 6-methyl-2-benzylindanone 5-methylindanone 5 -methyl-6-methoxyindanone 5-methyl-7-chloroindanone4-methoxy-7-chloroindanone 4-isopropyl-2,7-dimethylindanoneS-nitroindanone 7 -nitroindanone 7-phenylind-anone Z-phenylindanone6,7-benzoindanone 75,6,7-trichloroindanone 5 -benzyloxyindanoneZ-n-butylindanone S-methylthioindanone 5-methoxy-7-nitroindanone6-meth0xy-2-methylindanone In a 500 ml. 3-necked flask is placed 36.2 g.(0.55 mole) of zinc dust and in a 250 ml. addition funnel is charged asolution of '80 ml. anhydrous benzene, 20 ml. of anhydrous ether, g.(0.58 mole) of p-anisaldehyde and 98 g. (0.5 5 mole) ofethyl-Z-bromopropionate. About 10 ml. of the solution is added to thezinc dust with vigorous stirring and the mixture is warmed gently untilan exothermic reaction commences. The remaining reactants are addeddropwise at such a rate that the reaction mixture is refluxing smoothlyon its own accord (ca. 30-35 min.). After addition is completed themixture is placed in a water bath and refluxed for 30 minutes. Aftercooling to 0, 250 ml. of 10% sulfuric acid is added with vigorousstirring. The benzene layer is extracted twice with 50 ml. portions of5% sulfuric acid and washed twice with 50 ml. portions of water. Theaqueous acidic layers are combined and extracted with 2X50 ml. ether.The combined etheral and benzene extracts are dried over sodium sulfate.Evaporation of solvent and fractionation of the residue through a 6"Vigreux column affords 89 g. (69% of the product,ethyl-2-hydroxy-2-(p-rnethoxyphenyl)-1- methylpropionate, B.P. 165-160(1.5 mm.).

By the method described in Vander Zanden, Rec. trav. chirn., 68, 413(1949), the above compound is converted to 6 -methoxy-2-methylindanone.

EXAMPLE 2 EthyZ-S-methoxy-Z-methyl-3-indenyl acetate A solution of 13.4g. of 6-methoxy-2 methylindanone and 21 g. of ethyl bromoacetate in 45ml. benzene is added over a period of 5 minutes to 21 g. of zinc amalgam(prepared according to Org. Syn. Coll., vol. 3) in ml. benzene and 40ml. dry ether. A few crystals of iodine are added to start the reaction,and the reaction mixture is maintained at reflux temperature (ca. 65)with external heating. At 3 hour intervals two batches of 10 g. zincamalgam and '10 g. bromoester are added and the mixture is then refluxedfor 8 hours. After addition of 30 ml. of ethanol and ml. of acetic acid,the mixture is poured into 700 ml. of 1:1 aqueous acetic acid. Theorganic layer is separated, and the aqueous layer is extracted twicewith ether. The combined organic layers are washed thoroughly withWater, ammonium hydroxide and water. Drying over sodium sulfate,evaporation of solventlin vacuo followed by pumping at 80 (bath temp.)(1-2 mm.) gives a crude ethyl-(1-hydroxy-2-methyl-6- methoxy-indenyl)acetate (0a. 18 g.).

A mixture of the above crude hydroxyester, 20g. of p-toluenesulfonicacid monohydrate and 20 g. of anhydrous calcium chloride in 250 ml.toluene is refluxed overnight. The solution is filtered and the solidresidue is washed with benzene. The combined benzene solution is washedwith water, sodium-bicarbonate, water and then dried over sodiumsulfate. After evaporation the crude ethyl-S-methoxy 2 methyl 3 indenylacetate is chromatographed on acid-washed alumina and the product iseluted with petroleum ether-ether (v./v. 50l00%) as a yellow oil (11.8g., 70%).

EXAMPLE 3 6-methoxy-Z-methylindanonea-Methyl-/8(p-methoxyphenyl)propionic acid (15 g.) is added to g. ofpolyphosphoric acid at 50 and the mixture is heated at 83-90" for twohours. The syrup is poured into iced water, stirred for one-half hourand then extracted with ether three times. The ethanol solution iswashed with water twice and NaHCO five times until all the acidicmaterial has been removed. The remaining neutral solution is washed withwater and dried over sodium sulfate. Evaporation of the solution gives9.1 g. of the indanone as a pale yellow oil.

EXAMPLE 4 u-Methyl-B-(p-methylthiophenyl)propionic acid To a solution of2.3 (0.11 mole) of sodium in 100 ml. of absolute alcohol is added 17.4g. (0.1 mole) of diethyl methylmalonate and 17.3 g. (-0.1 mole) ofp-methylthiobenzylchloride. The mixture is heated under a reflux in awater bath for three hours. The reaction mixture is poured into waterand the aqueous solution is extracted six times with ether and dried. Itis then evaporated to yield diethyl methyl-p-methylthiobenzyl malonate.The crude product is then saponified by heating with excess 4% sodiumhydroxide in aqueous ethanolic solution. The solution thus formed isconcentrated, extracted with ether to remove-any neutral material, andacidified with dilute sulfuric acid. The acidic mixture is heated on asteam bath for one hour, cooled and then extracted with ether.Evaporation of the ether solution givesu-methylfl-(p-methylthiophenyl)propionic acid.

EXAMPLE 5 Ethyl-3-hya'roxy-Z-methyl-5-nitro-3-indany[acetate Theprocedure of Example 12 is followed using Z-methyl- 6-nitro indanone inequivalent quantities in place of 6- methoxy-2-methyl indanone usedtherein. After the mixture is condensed, 30 m1. of ethanol and 50 ml. ofacetic acid are added. The mixture is then poured into 700 ml. of water.Extraction with ether gives ethyl-3- hydroxy-Z-methyl-5-nitro-3-indanylacetate.

EXAMPLE 6 E thyl-5 -dimethylamina-3-hydr0xy-2-methyl-3 indanylacetate Asolution of 0.05 mole of ethyl-3-hydroxy-2-methyl-5-nitro-3-indanylacetate, 0.2 mole of 38% aqueous formaldehyde and 2 ml.of acetic acid in 100. ml. ethanol is reduced catalytically in thepresence of a Pd/C catalyst under 40 lb. p.s.i hydrogen presence at roomtemperature. The solution is filtered, evaporated and chromatographed on300 g. of silica gel to give ethyl-5-dimethylamino-3-hydroxy-2-methyl-3-indanylacetate.

EXAMPLE 7 Ethyl-S-nitro-Z-methyl-3-indenylacetate EXAMPLE 8I-p-chlorobenzylia'enyl-5-methoxy-2-methyl-3-indenyl acetic acid To asolution of 1.35 g. of ethyl(S-methoxy-Z-methyl- 3-indenyl)acetate in7.0 ml. dry dirnethoxyethane is added 0.80 g. of p-chlorobenzaldehydefollowed by 0.635 g. of potassium tertiary butoxide with ice-cooling andstirring. Upon addition of the base the light yellow color turns to anintense purple color. The reaction mixture is stirred at 0 for 4 hours,during that interval the color changes to light brown and an insolublepotassium salt gradually separates out. The reaction mixture is stirredat room temperature overnight and it becomes a thick paste. Theprecipitate (very fine particle) is centrifuged and washed with 3 ml. ofdimethoxyethane. The pale yellow precipitate is dissolved in a smallamount of hot water and acidified with dilute hydrochloric acid. Theyellow solid is filtered and dried at 70 (1 mm.), g. The crude acid isdissolved in 10 ml. methanol wtih gentle warming. On cooling to roomtemperature a first crop (0.61 g.) is recovered as fine needles. Themother liquor is concentrated in vacuo to 5 ml. which on cooling in arefrigerator gives a second crop of 0.15 g. The combined 2 crops ofproduct, M.P. 153-166" (believed to be methanol solvated) isrecrystallized once more from 5 ml. of methanol and then from 4 ml.benzene (dissolved with warming) plus 2 ml. of Skelly-solve B. Oncooling to 0, 440 mg. of the pure acid, M.P. 167-168 is obtained aslight yellow prisms, U.V. absorption: A 2400, 2880 and 3400. E% 628, 450and 405.

EXAMPLE 9 1-p-chl0r0benzylidene-j-dimethylamin0-2-methyl-3- indenylacetic acid To a solution of 2.5 g. of the ester from Example 6 in 15ml. of 1,2-dimethoxyethane at 0 is added 1.4 g. of p-chlorobenzaldehydefollowed by 1.1 g. of potassium t-butoxide. The reaction mixture is keptin the ice-bath EXAMPLE 101-benzylia'ene-5-methoxy-Z-methyl-.i-indenylacetic acid A solution of1.98 g. (0.009 mole) of S-methoxy-Z- methyl-3-indenylacetic acid (M.P.172) from saponification of the corresponding ethyl ester describedabove, in 25 ml. of 1,2-dimethoxyethane is added dropwise to asuspension of sodamide (from 0.46 g. sodium) in 250 ml. of liquidammonia. The mixture is stirred for 20 minutes and then a solution of1.00 g. of benzaldehyde in 5 ml. of 1,2-dimeth0xyethane is added. After3 hours, 1.24 g. of ammonium chloride followed by 10 ml. of water isadded to decompose the reaction mixture. The mixture is poured intowater and extracted with ether. The aqueous phase is acidified withhydrochloric acid to yield 2.7 g. of the product. Recrystallization fromethyl acetate-petroleum ether gives purel-benzylidene-S-methoxy-2-methyl-3-indenylacetic acid, M.P. 162-1635".

- EXAMPLE 11 I-(p-methylbenzylidene)-5-methoxy-2-methyl-3-indenylaceticacid When p-tolualdehyde is used in place of benzaldehyde in the aboveExample 10, there is obtained l-(p-methylbenzylidene)-5-methoxy 2 methyl3 indenyl acetic acid, M.P. 174-176".

EXAMPLE 12 S-methoxy-I-0x0-3-indanyl-acelic acid ml. The ether layer iswashed with water and dried over sodium sulfate. Evaporation of solventand chromatography of the residue on a silica gel column (1 lb.) givesS-methoxy-1-oxo-3-indanyl acetic acid.

The acid is converted to its methyl ester with methanolic hydrogenchloride in the usual manner.

EXAMPLE l3 1-p-chl0r0benzylidene-S-meth0xy-3-indanylacctic acid Asolution of freshly prepared n-butyl lithium (0.1

mole) in 60 ml. of ether is added dropwise to a mixture of 0.1 mole oftriphenyl p-chlorobenzyl phosphonium bromide, prepared in a manneraccording to Bergmann and Dueza, Ann. 603, 36 (1957), and 500 ml. ofether under nitrogen, After stirring one hour at room temperature, 0.09mole of the above indanylacetate in 50 ml. ether is added and themixture is heated in a bomb at 50-80 for 2-4 hours. After cooling thesolution is filtered, washed with Water, dried over sodium sulfate andevaporated to a syrup. The crude product is chromatographed on 600 g. ofacid-washed alumina using a mixture of ether-petroleum ether (v./v.20-50%) as eluent.

saponification of the above ester with 0.1 N sodium hydroxide in 90%aqueous ethanol at room temperature for- 18 hours gives thecorresponding acid, l-p-chlorobenzylidene-5-methoxy-3-indanylaceticacid.

EXAMPLE 14 1- (p-chlorobenzylidene -5-hydr0xy-2-melhyl-3-indenyl aceticacid EXAMPLE 15 a-(5-meth0xy-2-methyl-3-indenyl) propionic acid Theprocedure of Example 2 is followed using ethyl a-bromopropionate inequivalent quantities in place of ethyl bromoacetate used therein. Thereis obtained ethyl a-(l-hydroxy 6 methoxy 2 methyl-1-indanyl)propionateand it is then dehydrated to ethyl a-(5-methoxy-2-methyl-3-indenyl)propionate in the same manner. The U.V. spectrum ofthe product shows A 2210, 2610, 2930 and 3040. A, E% 709, 221, 115 and107.

The above ester is saponified to give a-(5-methoxy-2-,

methyl-3-indenyl)propionic acid, U.V. absorption: k 2210, 2625, 2930,3040. A, E% 795, 301, 132 and 128.

EXAMPLE 16 fluxing 4.5 hours with 150 cc. anhydrous methanol and 5 cc.concentrated H 50 The methanol solution is concentrated to 20 cc. andpoured into ether and water. The ether layer is washed with water,bicarbonate and carbonate solutions, water, and dried over Na SO Thesolution is filtered and 10 g. silica gel added and the mixtureconcentrated to dryness on a rotary evaporator. This solid is placed ona column of 200 g. silica gel and eluted with 1:1 benzene CHCl Eachfraction is ca. 80 cc. Fraction 16-25 yields 250 mg. of the pure methylester as a yellow oil. Yield: 250-260 mg. of a yellow oil. Qual. U.V. A3410, 2875, 2380 A.

To this oil in 3.9 cc. EtOH is added 0.3 cc. 11.7 N NaOH and 0.3 cc. H0, and the mixture is stirred at room temperature under a nitrogenatmosphere for 18 hours; The saponification mixture yields 235 mg. ofcc- (1 p chlorobenzylidene-5-methoxy-2-methyl-3-indenyl) propionic acidas a yellow solid. U.V. absorption: i 2410, 2880 and 3440 A; E% 542, 509and 370. Calcd. for C H ClO C, 70.27; H, 5.30; CI, 10.37. Found: C,69.56; H, 5.61; Cl, 10.68.

EXAMPLE 17 oc- [1- (p-methylthiobenzylidene -2-m'ethyl-5-methoxy-3-indenyl1-pr0pi0nic acid To a solution of 0.5 g. (0.00192 mole) ofethyl-u-[Z- I rnethyl-5-methoxy-3-iudenyl]-propionic acid and 0.595 g.

a- (1-p-chlorobenzylidene-S-methoxy-Z-mthyl-S-indenyl propionic acid To1.0 g. of a-(5-methoxy-2-methyl-3-idenyl)-propionic acid in 4.5 cc. ofCaH dried DME at 0 is added 0.572 g. (0.004 mole) ofp-chlorobenzaldehyde followed by 0.46 g. of potassium t-butoxide. Animmediate purple color is observed. The mixture is kept at thistemperature 3.5 hours, then allowed to stand at room temperature for 2days.

The reaction mixture is poured into water acidified with 2.5 N HCl, andextracted with ether. The ether solution is then extracted with 5% Na COsolution. The carbonate solution. is filtered, then acidified with 2.50HCl, extracted with Et O. The ether solution is washed with water anddried over sodium sulfate. The ether solution is then filtered,converted to a yellow oil and the yellow oil converted to the methylester by re- (0.0039 mole) of pmethylthiobenzaldehyde in 3 ml. ofanhydrous pyridine is added 1.63 g. of a 40% solution ofbenzyltrimethylammonium hydroxide (Triton-B) in methanol. The resultingred-purple solution is allowed to stir at room temperature overnight.

The mixture is poured into a mixture of ice and water, acidified in 2.5N HCl, and extracted with ether. The ether solution is then washed with2.5 N HCl till washing acidifies (once), then with water till neutral.The ether, layer is then extracted with 5% Na CO solution. The Na COsolution iswashed with ether, acidified and extracted with ether. Ethersolution is washed with water, dried over Na CO and concentrated invacuo to a yellow oil which foams up to a clear yellow solid on pumpingat 0.5-1 mm. Yield: 650 mg. (93%). Thin layer chromatography of theproduct shows only one spot when eluted with a (v./v. 4:325 ofisopropanol: 10% NH OH: ethyl acetate mixture:

U.V. absorption k 3525; 2910, 2540; 2450; E% 399; 260, 510 and 498.

EXAMPLE 18 1-p-chlor0benzylidene-Z-methyl-5-methoxy-3indenylacetmorpholide A mixture ofl-p-chlorobenzylidene-2-methyI-S-methoxy-3-idenylacetic acid (0.01 mole)and thionyl chloride (0.03 mole) in a dried flask, condenser and dryingtube set-up is heated on the steam bath until evolution of gas ceases.Excess thionyl chloride is then removed in vacuo, the residue taken upin a slight excess of anhydrous ether and added slowly to a vigorouslystirred, ice-cooled solution of dry morpholine (0.035 mole) in ml. ofether. The mixture is stirred overnight at room temperature, filtered,the morpholine hydrochloride washed with excess ether, and the combinedether filtrates washed with 2 x100 ml. water, dried over anhydroussodium sulfate, filtered, and the ether removed in vacuo. Chromatographyof the crude product on a silica-gel column, using v./v. 50100% ether inpetroleum ether as eluent gives the desired morpholide.

Similarly, when morpholine is replaced by an equivalent amount of thefollowing amines, the corresponding amides are obtained.

Dimethylamine Ethanolamine Benzylamine N,N-dicthylethylenediamine r 13Benzylglycinate Piperidine Pyrrolidine N-methylpiperazineN-phenylpiperazine N-hydroxyethylpiperazine Piperazine DiethylamineDiethanolamine Aniline p-Ethoxyaniline p-Chloroaniline p-Fluoroanilinep-Trifluoromethylaniline Butylamine Cyclohexylamine MethylamineD-glucosamine Tetra-o-acetyl-d-glucosamine D-galactosylamineD-mannosylamine N,N-dimethyl-glycine amide N,N-dibutylglycine amideN-methyl-2-aminomethylpiperidine N-methyl-2-aminomethylpyrrolidineB-Ethoxyethylamine Di S-ethoxyethyl) amine fl-Phenethy-laminetz-Phenethylamine Dibenzylamine D-mannosamine EXAMPLE 19 Esters of1-p-chlorobenzylidene-Z-methyl-5-meth0xy-3- indenyl acetic acid ethanoland 75 ml. ofdry benzene is refluxed on a steam bath while slowlydistilling the solvent. After 17 hours the residual solvent is removedunder reduced pressure. The residue is sl-urried in aqueous sodiumbicarbonate and then with Water until neutral. The resulting ethyl estermay be recrystallized from organic solvents such as ethyl acetate,benzene and the like. When methanol,,propanol, t-butanol and benzylalcohol are used instead of the ethanol in the above procedure, there isobtained the corresponding methyl, propyl, t-butyl and benzyl esters.

(B) Alkoxyalkyl esters.-Chloromethyl methyl ether (0.055 mole) is addedto a suspension of l-p-chlorobenzylidene-2-methyl-5-methoxy-3-indenylacetic acid (0.05 mole) and anhydrous potassium carbonate (0.15 mole) in250 ml. of anhydrous acetone. to stir overnight at room temperature.Diethyl ether is added (about 200 ml.) and the mixture is filtered. Thefiltrate is washed once with 100 ml. of saturated sodium bicarbonatesolution and twice with 100 ml. of Water and dried over anhydrous sodiumsulfate. It is then filtered and the solvent is removed in vacuo. Theresidue is chromatographed on 200 g. of acid-washed alumina, usingether-petroleum ether (varying from 10 to 60% ether by volume) as theeluant, to give methoxymethyll-p-chlorobenzylidene-Z-methyl-5-methoxy-3-indenyl-acetate.

(C) Dialkylamino-alkyl esters-A solution of 0.0054 mole ofN,N'-dicyclohexylcarbodiimide in 6 ml. of anhydrous tetrahydrofuran isadded to a solution of l-pchlorobenzyl 2methyl-5-methoxy-3-indenylacetic acid (0.005 mole) andZ-diethylaminoethanol (0.0054 mole) in 17 ml. of anhydroustetrahydrofuran. The mixture is stirred at ambient temperature,overnight. The dicyclohexylurea is removed by filtration and 2 ml. ofglacial acetic acid is added to the filtrate. After the mixture hasstood for one hour, it is filtered and 200 ml. of ether is added to thefiltrate. The solution is then ex- The mixture is allowedtracted threetimes with 100 ml. of 2.5 N HCl and the extracts are combined, washedtwice with 100 ml. of ether, ice-cooled, made slightly alkaline withconcen trated NH OH and extracted three times with 100 ml. of ether. Theether extracts are combined, washed ten times with 100 ml. of water toremove traces of starting amine, dried over anhydrous potassiumcarbonate, filtered and evaporated in vacuo. The oily residue is[it-diethylaminoethyl 1 pchlorobenzylidene-Z-methyl-S-methoxy-3-indenylacetate.

When 2 dimethylaminoethanol, 3-dimethylamino-1- propanol,S-diethylaminol-propanol, N-B-hydroxyethylpiperidine,N-fl-hydroxyethylpyrrolidine, N-hydroxymethylpyrrolidine,N-methyl-Z-hydroxymethylpyrrolidine, N- ethyl 2 hydroxymethylpiperidine,1- 3-hydroxyethyl-4'- methyl-piperazine or N-B-hydroxyethyl morpholineis used in the above procedure in place of Z-diethylarninoethanol, thecorresponding ,8dimethylaminoethyl, 'y-dlmethylaminopropyl,'y-diethylaminopropyl, p-N-piperidinylethyl, ,B-N-pyrrolidinylethyl,N-pyrrolidinylmethyl, 2'- (1 methylpyrrolidinyl-methyl),4-methyl-1-piperazinylethyl, N-ethyl-Z-piperidinylethyl andN-morpholinylethyl esters are obtained.

(D) Phenyl 1 p chlorobenzylidenyl-Z-methyl-S-methoxy-3-indenylacetate.Asolution of 0.0054 mole. of N,N-dicyclohexylcarbodiimide in 6 ml. ofanhydrous tetrahydrofuran is added to a solution ofl-p-chlorobenzylidenyl 2 methyl-5-methoxy-3-indenylacetic acid (0.005mole) and phenol (0.0054 mole) in 17 ml. of anhydrous tetrahydrofuran.The mixture is shaken vigorously and allowed to sit, stoppered, at roomtemperature overnight.

After filtering ofl? the N,N'-dicyclohexylurea, 2 ml. of glacial aceticacid is added to the filtrate and the mixture allowed to stand one hour.After filtering, 200 ml. ether is added to the filtrate and the ethersolution washed with 2x100 ml. saturated sodium bicarbonate solution and3 x100 ml. water and then dried over anhydrous sodium sulfate. Themixture is filtered, concentrated in vacuo to 25 ml. and chromatographedon a 150 g. acid-washed alumina column using ether-petroleum ether(v./v. 10- 60%) as eluent to give phenyl-l-p-chlorobenzylide'nyl-2-methyl-5-methoxy-3-indenylacetate.

Similarly, using 2(2-methoxyethoxy)-ethanol, glycol orN-acetyl-ethanolamine in place of phenol in the above procedure gives 2(Z-methoxyethoxy)-ethyl-1-p-chlorobenzylidenyl 2methyl-5-methoxy-3-indenylacetate, [-1- hydroxyethyl 1 pchlorobenzylidenyl 2 methyl- 5 methoxy-3-indenylacetate andfl-acetamidoethyl-l-pchlorobenzylidenyl 2methyl-5-methoxy-3-indenylacetate, respectively.

A mixture of .06 mole of sodium l-p-chlorobenzylidene-2methyl-5-methoxy-3-indenyl acetate and 0.05 mole of trit'yl bromide inml. anhydrous benzene is refluxed with rapid stirring under nitrogen for5 hours. The hot reaction mixture is filtered and the filtrate isconcentrated in vacuo. The residual oil is recrystallized from methylethyl ketone to give trityl-l-p-chlorobenzylidene-2-methyl-5-methoxy-3-indenyl acetate.

When any of the other 3-indenyl acids described in other examples areused in place of the above-described acid in any of the abovepreparations, the corresponding esters are obtained.

EXAMPLE 20 N-(I-p-chlorobenzylidene-2-methyl-5-methoxy- 3-indenylacetyl) -glycine (A)Benzyl-N-(1-p-chlorobenzylidene-Z-methyl-5-meth0xy-3-indenylacetyl)-glycinate.The procedure of Example 18 is followed usingbenzylamino acetate in place of the morpholine to produce theabove-named compound.

(B) N-(1-p-chlorobenzylidene-Z-methyl-5-meth0xy-3 indenylacetyl)glycine.Benzyl N l-p-chlorobenzylidene 2 methyl 5methoxy-3-indenylacetyl)glycinate (0.003 mole) in a mixture of 25 ml. ofanhydrous. ethanol and 2.5 ml. of 1 N sodium hydroxide is allowed tostand at room temperature for 18 hours. The solution is diluted withwater and extracted with ether. The aqueous layer is acidified withdilute hydrochloric acid and the organic product is extracted with ethylacetate, washed with water and dried over sodium sulfate. Evaporation ofthe solution gives N-(l-p-chlorobenzylidene-2-methyl-5-methoxy-3-indenylacetyl) glycine.

When any of the other l-aralkylidene-3-indenyl aliphatic acids describedin the other examples of these specifications are used in the aboveprocedure in place of thel-p-chlorobenzylidene-2-methyl-5-rnethoxy-3-indenyl acetic acid, thecorresponding indenyl acyl glycine is obtained.

EXAMPLE 21 (A) Ethyl-4-flu0r0-a-methylcinnamate.-Into a dry l-liter3-neck round bottom flask equipped with stirring, thermometer andnitrogen inlet tube is charged sodium hydride (0.384 mole). Ethylpropionate (1.45 mole) is added, the temperature kept at ca. C. with aDry-Iceacetone bath. Absolute ethanol (0.48 ml.) is then added, followedby a mixture of ethylpropionate (0.78 mole) and p-fiuorobenzaldehyde(0.322 mole) added at such a rate that the temperature stays at 20 C.The mixture is cooled to 15, the Dry-Ice-acetone bath replaced by an icebath, and the mixture stirred one hour. A solution of 29.2 ml. ofglacial acetic acid in 108 ml. water isadded, the mixture stirred ca. 15minutes, transferred to a separatory funnel, the layers separated, andthe aqueous layer extracted with 2X54 ml. ether. The ether and organiclayers are combined, washed with 2X 36 ml. waterand 3X97 ml. 10% aqueouspotassium carbonate solution, dried over anhydrous potassium carbonate,filtered, and the solvent removed in vacuo. Distillation of the oilyresidue in vacuo gives ethyl-.4- fluoro-a-methylcinnamate, B.P. 12513l;5-6 mm.

Similarly, the use of o-fluorobenzaldehyde, m-fluorobenzaldehyde orp-trifiuoromethylbenzaldehyde in place of p-fluorobenzaldehyde in theabove procedure gives ethyl 2-fiu-oro-a-methylcinnamate,ethyl-3-fluoro-a-methylcinnamate, andethyl-4-trifluoromethyl-a-methylcinnamate, respectively.

(B) 4-flu0r0-a-methylcinnamic acid.-To a solution ofethyl-4-fiuoro-e-methylcinnamate (0.01 mole) in 25 ml. of ethanol isadded a solution of potassium hydroxide (0.01 mole) in 5 ml. water andthe mixture stirred overnight at room temperature under a nitrogenatmosphere. Water (ca. 100 ml.) is added, the aqueous mixture washedwith 3x100 ml. ether, ice-cooled and acidified with 2.5 N hydrochloricacid, and extracted with 3x100 ml. ethyl acetate. The combined ethylacetate extracts are washed with 2X 100 ml. water, dried over anhydroussodium sulfate, filtered, and the solvent removed in vacuo leaving4-fluoro-a-methylcinnamic acid, M.P. l51-153 C. (from ethanol).

Similarly, using ethyl-Z-fiuoro-a-methylcinnarnate, ethyl-3-fluoro-a-methylcinnamate, or ethyl-4-trifluoromethyl-amethylcinnamatecinnamate in the above procedure gives 2-fiuoro-a-methyl cinnamic acid,3-fluoro-wmethylcinnamic acid and 4-trifluoromethyl-u-methylcinnamicacid, respectively.

(C) 4-fluoro-a-methylhydrocinnamic acid.A solution of4-fluoro-a-methylcinnamic acid (0.23 mole) in 800 ml. of anhydrousethanol is reduced at room temperature under a hydrogen pressure of 40p.s.i. in the presence of 2 g. 5% palladium on carbon. After filtering,the ethanol is removed in vacuo, several 40 ml. portions of benzeneadded and distilled away to remove moisture, and the oily residue driedin vacuo leaving 4-fluoro-a-methylhydrocinnamic acid.

Similarly, reduction of 2-fluoro-a-methylcinnamic acid,3-fluoro-u-methylcinnamic acid, and 4-trifluoromethyl-ain place ofethyl-4-fluoro-ot-methyl-' 16 methylcinnamic acid using the aboveprocedure gives the corresponding hydrocinnamic acid derivative.

(D) 2-methyl-o-fluoroindanone-l.-The procedure of Example 3 is followedusing 4-fluoro-a-methylhydrocinnamic acid in place of the methylmethoxyphenyl propionic acid used there, to yield2-methyl-6-i'luoroindanone-l.

Similarly, 4-fiuoro-2-rnethylindanone-l, S-fluoro-Z- methylindanone-l,and 6-trifluoromethylindanone-l, are obtained via the above procedure(followed by chromatography on an acid-washed alumina column [v./v.1:30] using ether-petroleum ether [v./v. 060%] for the5-fluoro-2-methylindanone-l) from 2-fiuoro-ix-methylhydrocirinamic acid,3-fiuoro-a-methylhydrocinnamic acid, and4-trifluoromethyl-a-methylhydrocinnamic acid, respectively.

EXAMPLE 22 E thyl-2-methyl-5 -flu0r0-3-indeny lace tale The procedure ofExample 2 is followed using 2-methyl- 6-fluoroindanone-1 in place of6-rnethoxy-2-methylindanone. The product is ethyl-2-methyl-5-fiuoro-3-indenylacetate.

Similarly, the use of 4-fiuoro-2-methylindanone- 1,

S-fluoro-2-methylindanone-l, or 6-trifluoromethyl-2-methylindanone-l, inplace of 2-methyl-6-fiuoroindanone-l in the above procedure givesethyl-2-methyl-7-fluoro-3- indenylacetate,ethyl-2-methyl-6-fluoro-3-indenylacetate,

and ethyI-Z-methyl-S-trifluoromethyl-3-indenylacetate, re-

spectively.

EXAMPLE 23 1 -p-chlorobenzylidene-Z-methyl-5-fluor0-3- indenylaceticacid indenylacetate in the same procedure gives l-p-chlorobenzylidene 2methyl 6 fluoro 3 indenylacetic acid, 1 p chlorobenzylidene 2 methyl 7fluoro- B-indenylacetic acid, and l p chlorobenzylidene 2- methyl 5trifiuoromethyl 3 indenylacetic acid, respectively.

When the procedure of Example 8 is followed as in Part A, but using inaddition, p-methoxybenzaldehyde in place of p-chlorobenzaldehyde, thereis obtained 1 prnethoxybenzylidene 2 methyl 5 fluoro 3 indenylaceticacid.

EXAMPLE 24 1-p-chlorobenzylidene-2-phenyl-5-meth0xy-3- indenylaceticacid Theprocedure of Example 2 is followed using 2-phenyl-6-methoxy-indanone-l in place of 6-methoxy-2-methylindauone to giveethyl 2 phenyl-S-methoxy-3-indenyl acetate. When this is used in theprocedure of Example 8, there is obtained 1 pchlorobenzylidene-Z-phenyl-5- methoxy-3-indenylacetic acid. When2-phenylindanone-1 is used as the starting material in place of2-phenyl-6- methoxyindanone, there is obtainedl-p-chlorobenzylidene-Z-phenyl-S-indenylacetic acid.

When 2-thienyl-6-methoxyindanone-1 (prepared by Claisen condensation ofanisaldehyde on ethyl thienyl-2- acetate, followed by catalyticreduction over palladium and ring closure with polyphosphoric acid) isused in the above procedure in place of theZ-phenyl-fi-methoxyindanone-l, the corresponding 2-thienyl compound isobtained.

1 7 EXAMPLE 2s The procedure of Example 21A is followed, usingpmethoxybenzaldehyde as the reagent to obtain ethyl-4-methoxy-wbenzylcinnamate. This compound is used in the procedure ofExample 21B; the product therefrom is used in the procedure of Example210 and the resulting product is then used in the procedure of Example21D. The compound thus prepared is the intermediate2-benzyl-6-methoxyindanone-1. When the known compound,a-benzylhydrocinnamic acid is used in the procedure of Example 21D,there is obtained 2-benzylindanone-l.

The procedure of Examples 22 and 23 is followed using the2-benzylindanones prepared above as the starting material. The compoundsthus obtained arel-p-chlorobenzylidene-Z-benzyl-S-methoxy-3-indenylacetic acid and1-p-chlorobenzylidene-2-benzyl-3-indenylacetic acid.

EXAMPLE 26 2-methoxy-4-methyl-indan0ne-1 A solution of 0.05 mole of 2hydroxy 4 methyl indanone and 0.055 mole of potassium t-butoxide in 250ml. dimethylformamide is treated with 0.06 mole of methyl iodide at roomtemperature for 18 hours. The reaction mixture is diluted with 700 ml.of water and extracted with ether (2x300 ml.). The ethereal solution isdried over sodium sulfate, evaporated to a syrup, and chromatographed on200 g. of acid-washed alumina using ether-n-hexane (v./v. 20-50%) aseluents to give 2-methoxy-4-methyl-indanone-1.

EXAMPLE 27 1-p-chl0r0benzylidene-Z-methoxy-7-methyl-3- indenylaceticacid (A) Ethyl (1 hydroxy-2-methoxy-4-methyl-Indenyl) acetate-When2-methoxy-4-methyl-indanone-1 is used in Example 2 in place of6-methoxy-2-methy1-indanone-l, there is obtainedethyl-(l-hydroxy-2-methoxy-7-methylindenyl)acetate.

(B) Ethyl 2 methxy-7-methyl-3-indenyl acetate.- To a solution of theabove hydroxy ester (0.05 mole) and pyridine (0.06 mole) in 200 ml.ether is added dropwise with ice-cooling and stirring 0.055 mole ofmethyl chlorosulfinate. After the addition is completed, the mixture isstirred at room temperature for 4 hours and filtered. The filtrate iswashed with 0.1 N hydrochloric acid, with water and then with sodiumbicarbonate. After drying over sodium sulfate, the solvent is evaporatedin vacuo, and the residue is pyrolyzed under nitrogen in the presence of0.5 ml. of quinoline at (oil bath temperature) 160-240". The pyrolysisproduct is redissolved in ether, washed with water and dried over sodiumsulfate. Evaporation of the solvent and chromatography of the residue on200 g. of acid-washed alumina, using ether-n-hexane (v./v. 20.-60%) aseluent, gives ethyl-Z-methoxy-7-methyl-3-indenyl acetate.

(C) I p chlorobenzylidenyl-2-meth0xy-7-methyl-3- indenylacetic acid.Whenthe above indenyl ester is used in place ofethyl-'(5-methoxy-2-methyl-3-indenyl) acetate in Example 8, there isobtained 1-p-chlorobenzylidene-2- methoxy-7-methyl-3-indenylacetic acid.

(D) 1 p chlorobenzylidene 2 hydroxy-7-methylindenylacetic acid.Theproduct of Part C is used in the procedure of Example 14 in place of thel-p-chlorobenzylidene-2-methyl-5-methoxy-3-indenylacetic acid usedtherein, to form 1-p-chlorobenzylidene-2-hydroxy-5-methyl-3-indenylacetic acid.

EXAMPLE 28 I-p-chlorobenzylidene-5-phenyl-3-indeny[acetic acid Theprocedure of Example 21C is followed, using pphenylciunamic acid inplace of the a-methyl-4-fiuorocinnamic acid used therein. The resultinghydrocinnamic acid is used in the procedure of Example 3 to form 6-phenylindanone-l. This compound is then used in the procedure of Example2 to produce ethyl-6-phenyl-3- indenyl acetate. This ester is condensedwith p-chloro= benzaldehyde in the procedure of Example 8 to form thedesired 1 p-chlorobenzylidene-5-phenyl-3-indenylacetic acid.

When 7-phenylindanone-l is used in the procedure of Example 2 and theproduct is condensed with p-chlorobenzaldehyde in the procedure ofExample 8, there is obtained 1 pchlorobenzylidene-4-phenyl-3-indeny1acetic acid.

EXAMPLE 29 (A) 1 p chlorobenzylidene 2-phenylthio-3-indenyh aceticacid.Following the procedure of Example 2, 2- phenylthio indanone-l isconverted to ethyl-Z-phenylthio- 3-idenylacetate. This ester iscondensed with p-chlorobenzaldehyde in the procedure of Example 8 toform the desired 1-p-chlorobenzylidene-Z-phenylthio-3-indenylaceticacid.

(B) 1 p chlorobenzylidene-Z-methylthi0-5-methoxy- 3-indenylaceticacid.-2 bromo-6-methoxyindanone (0.1 mole) dissolved in 150 ml. drymethanol is added slowly, in an atmosphere of nitrogen, to a solution ofsodium thiomethoxide prepared from 2.5 g. sodium and ml. dry methanolcontaining 0.1 mole of methylmercaptan. The solution is refluxed for onehour, concentrated in vacuo, poured into water and then extracted withether. The ethereal solution is washed with water and dried over sodiumsulfate. Evaporation of the solvent followed by chromatography on 300 g.of acid-washed alumina, using ether-n-hexane (v./v. 10-50%) aseluent,gives Z-methylthio-6-methoxy indanone.

Using the procedure of Examples 2 and 8, the above indanone is convertedsuccessively to ethy1-(5-methoxy)- 2-methylthio-3-indenylacetate andl-p-chlorobenzylidene- 5-methoxy-2-methylt=hio-3-indenyl acetic acid.

EXAMPLE 301-p-chl0r0benzylidene-Z,6-dimethyl-3-indenyl-adimethylaminoacetic acid(A) Ethyl 2,6 dimethy[-3-indenyl-a-aminoacetate.- A mixture of 0.01 moleof ethyl-2,6-dimethyl-3-indenylglyoxalate (prepared from2,6-dimethylindene and oxalic ester by the procedure of Thiele, Ber. 33,851 (1900) hydroxylamine hydrochloride (0.026 mole), ethanol (20 ml.)and 5 ml. of pyridine is heated on a steam bath under nitrogen for 3hours. The mixture is concentrated in vacuo to about 10 ml. and pouredinto 250 ml. of ice and water. After the ice has melted, the organicmaterial is collected, washed well with water until the odor of pyridineis gone, and dried. The product is dissolved in 25 ml. of ethanol and0.03 mole of glacial acetic acid is i added. Zinc dust (0.012 mole) isadded gradually and the mixture is warmed gently until all the zinc isdissolved. The mixture is filtered and 50 ml. of 2.5 N HCl is added. Theaqueous phase is washed twice with 50 ml. of chloroform, cooled and madeslightly alkaline with concentrated NH OH. It is then extracted threetimes with 50 ml. of chloroform. These extracts are combined, washedwith 100 ml. of water twice and dried over K CO The solut-ion isfiltered and concentrated in vacuo to give ethyl-2,6-dimethyl-3-indenyl-a-amino acetate.

(B) Ethyl 2,6 dimethyl 3-indenyl-a-dimethylamino acetate.-A solution ofethyl- 2,6-dimethyl-3-indenyl-aamino acetate (0.05 mole) andmethyliodide (0.15 mole) in 100 ml. acetone is stirred at roomtemperature for 18 hours in the presence of excess (0.2 mole) potassiumcarbonate. The solution is filtered, concentrated in vacuo and pouredinto 300 ml. of water. The product is extracted with ether, washed withwater and dried over, sodium sulfate. The ethereal solution isevaporated to a syrup and chromatographed on 200 g. of neutral alumina,using ether-petroleum ether (B.P. 30-60) (v./v. 20-

19 100%) as eluents to give ethyl-2,6-dimethyl-3-indenyl-adimethylaminoacetate.

(C) 1 p chlorobenzylidenyl 2,6-dimethyl-3-indenyla-dimethylamino aceticacid.The procedure of Example 8 is followed using the aboveethyl-2,6-dimethyl-3-indenyl-ec-dimethylaminoacetate in place of theindenyl ester used therein. The product isolated is then purified bychromatography on a bed of thin plates of 8 inches by 8 inches crosssection coated with silica gel, using ethylacetate-l-propanol as theeluent, to produce l-p-chlorobenzylidenyl 2,6dimethyl-3-indenyl-u-dimethylaminoacetic acid.

EXAMPLE 31 1-p-chlorqbenzylidene-Z-methyl-5-methoxy-3-indenya-dimethylamin'oacetic acid (A) Z-methyl-5-meth0xyindene.(l) To amixture of 7.56 g. of sodium b-orohydr-ide and 200 ml. of isop'ropanolis added dropwise a solution of 0.2 mole of 2-methyl-6- methoxyindanonein 50 ml. isopropanol at room temperature over a period of one-halfhour. The mixture is then heated at the reflux temperature for 4-8hours, the reduction being followed by thin-layer chromatography. Aftercooling, the mixture is poured into one liter of iced water andextracted with 3 150 ml. of ether. The ethereal solution is washed withwater, dried over sodium sulfate, and evaporated to give crude2-methyl-6-methoxy-1- indanol.

(2) The above indanol (0.05 mole) is dissolved in a mixture of 25 ml.ether and 4.4 g. (0.055 mole) of pyridine. The solution is cooled to andto this is added slowly 5.8 g. (0.05 mole) methyl chlorosulfinate over aperiod of 20-25 minutes. After stirring at 05 for an additional 30-60minutes the mixture is poured into icedwater and extracted with ether.The ethereal solution is washed with 0.2 N hydrochloric acid, sodiumbicarbonate,

water and dried over sodium sulfate. The dried solution is evaporated toa residue. Pyrolysis of the residue under nitrogen with concomitantdistillation at bath temperature (100-310) under partial vacuum gives2-methyl-5-methoxyindene as a yellow liquid.

(B) Methyl-2-methyl-5 methoxy 3 indenyl glyoxalate-To a solution of 1 g.sodium in 20 ml. absolute ethanol is :added 7.5 g. of2-methyl-5-methoxyindene and 6 g. of dimethyloxalate. The solution isallowed to stand at room temperature for l-2 hours and is then warmed ona steam bath to complete the reaction. The mixture is cooled and pouredinto iced-water. After extraction with ether to remove the by-products,the aqueous layer is acidified to givemethyl-2-methy1-5-methoxy-3-indenyl glyoxalate.

(C) Ethyl-2-methyl-5-methoxy-3-indenyl-u dimethylaminoairetate-Theprocedure ofExamples 30A and 30B is followed successively, starting withthe product of Part B instead of the dimethyl-3-indenylglyoxalate esterused therein, to produce ethyl-2methyl-5-methoxy-3indenyl-ot-dimethylaminoacetate.

(D) 1-p-chl0r0benzylidene-2-methyl-5-meth0xy-3indenyl-a-dimethylaminoacetic acid.-The procedure of Example 8 isfollowed using the product of Part C in place of the indenyl acetateused therein to form l-p-chlorobenzylidene-Z-methyl--methoxyr3-indenylcc dimethylaminoacetic acid.

EXAMPLE 321-p-chlorobenzylidene-Z-methyl-5-methoxy-3-indenyl-umethoxyacetic acid a(A) MethyZ-S-meflwxy-Z-methyl -3 indenyl a hydr0xyacetate.-To a solutionof methyl 5 methoxy 2- methyl-3-indeny1glyoxalate (0.01 mole) in 50 ml.methanol is added portionwise 0.005 mole of sodium borohydride withice-cooling and stirring. After two hours at 0-5 and four hours at roomtemperature thereaction mixture is poured into iced water containing anexcess of 20 acetic acid. The product is extracted with ether and theethereal solution is washed with water, dried over sodium sulfate andconcentrated in vacuo. The residue is chromatographed on a silica gelcolumn (200 g.) using etherpetroleum ether (v./v. 50-l00%) as eluent togive methyl-5-methoxy-2-methyl-3-indenyl-a-hydroxyacetate.

(B) Methyl-5-meth0xy-2-methyl-3 indenyl on tosyl- 0xyacctate.To asolution of 0.02 mole of methyl-5-methoxy-2-methyl-3-indenyl-a-hydroxyacetate in ml. pyridine at 05 isadded 0.025 mole of p-toluenesulfonyl chloride portionwise. The mixtureis allowed to stand at 5lO for 18 hours :and is then poured into icedwater. The product is extracted with ether, washed with dilutehydrochloric acid, sodium bicarbonate, water and then dried over sodiumsulfate. Evaporation of the solvent and chromatography of the residue ona column of 500 g. silica gel, using benzene-petroleum ether (v./v.1050%) as eluent gives the desired sulfonate ester.

(C) Methyl-5-mcth0xy-2-methyl- 3 indenyl a meth0xyacetate.A solution of0.05 mole of methyl-5- methoxy-2-methyl-3-indenyl-a-tosyloxy acetate and0.05 mole sodium methoxide in 300 ml. methanol is heated under refluxfor 4- -8 hours under nitrogen until the solution becomes neutral. Themixture is concentrated in vacuo to ca. 100 ml., poured into water andextracted with ether. The ethereal solution is washed with water, driedover sodium sulfate and evaporated to a residue. The residue ischromatographed on a column of 500 g. of silica gel usingether-petroleum ether (v./v. 30l00%) as eluent to give the product,methyl-5-methoxy-2-methy1-3- indenyl-a-methoxyacetate.

(D) 1-chl0r0bcitzylidene-Z-mcthyl-S methoxy 3 indenyl-et-methoxy aceticacid.The procedure of Example '8 is followed, using the product of PartC in place of the indenyl ester used therein, to producel-p-chlorobenzylidene-2-methyl-5,a-dimethoxy-3-indenylacetic acid.

(E) 1-p-chlorobenzylidene-2-methyl-5-meth0xy-3 indenyl-u-hydroxyaceticacid.-The procedure of Example 8 is followed using the product ofExample 33A in place of the ethyI-Z-methyl-5-methoxy-3-indenylacetateand using twice the mole usage of potassium-t-butoxide. The productobtained is 1-p-chlorobenzylidene-2 methyl 5methoxy-3-indenyl-a-hydroxyacetic acid.

EXAMPLE 33 I (p-nitrobenzylia'ene -2-methyl-5-methoxy-3-indenylaceticacid The procedure of Example 8 is followed using p-nitrobenzaldehyde inplace of p-chlo-robenzaldehyde to yieldl-(p-nitrobenzylidene)-2-methy1-5 methoxy 3 indenyl acetate.

Similarly, the use of m-trifluoromethylbenzaldehyde or3,4-dichlorobenzaldehyde in place of p-nitrobenzaldehyde in the aboveprocedure gives l-(m-trifluoromethylbenzylidene)-2-methyl-5-methoxy 3indenylacetic acid and 1-(3,4-dichlorobenzylidene)-2-methyl-5 methoxy -3indenylacetic acid, respectively.

EXAMPLE 34 1- (3-nitroth'ienyl-2-formylidene -2-methyl-5-meth0xy-3-indenylacetic acid The procedure of Example 8 is followedusing nitrothiophene-2-carboxaldehyde in place of p-chlorobenzaldehyde,to yield1-(3nitrothienyl-2-formylidene)-2-methyl-5-methoxy-3-indenylacetic acid.

Similarly, using 2-thiophenecarboxaldehyde, 2-fu-raldehyde,N-methylpyrrolo-Z-aldehyde, thiazole-2-carboxaldehyde,pyridine-Z-aldehyde, pyridine-3-aldehyde, pyridine- 4-aldehyde,l-methylimidazole-S-aldehyde, l-methyl-indole-3-carboxaldehyde,N-me-thylpiperidine-4-carboxaldehyde, quinoxaline-Z-carboxaldehyde,5-chloro-3-benz0- furanecarboxaldehyde, 5-benzofurancarboxaldehyde, 3-thianaphthenecarboxaldehyde, 1-methylbenzimidazole-3- carboxaldehyde, 4H1 3 methyl 4 oxo 2 benzo EXAMPLE 35I-p-chlorobenzylidene-2-flu0r0-3-indenylacetic acid The procedure ofExample 2 is followed using 2-fluoro indanone in place of the indanoneused therein. The product is then used in the procedure of Example 8 togive 1-p-chlorobenzylidene-Z-fluoro-3-indenylacetic acid.

.EXAMPLE 36 Methyl-5-methcxy-2-methyl-3-indenyl-a-fluoro acetate Amixture of potassium fluoride (0.1 mole) andmethyl-5-methoxy-2-methyl-3-indenyl-a-tosyloxy acetate (0.05 mole) in200 ml. dimethylformamide is heated under nitrogen at the refluxtemperature for 2-4 hours. The reaction mixture is cooled, poured intoiced water and then extracted with ether. The ethereal solution iswashed with water, sodium bicarbonate and dried over sodium sulfate.Evaporation of the solvent and chromatography of the residue on anacid-washed alumina column (300 g.) using ether-petroleum ether (v./v.2050%) as eluent gives the product,methyl-.S-methoxy-Z-methyl-3-indenyla-fluoroacetate.

The above product is then used in the procedure of Example 8 to give1-p-chlorobenzylidene-2-methyl-5-methoxy-3-indenyl-u-fluoroacetic acid.

EXAMPLE 37 1-p-chlorobenzylideneJ-methoxy-2-methyl-3-indenyl-a-morpholinoacetic acid A solution ofmethyl-5-methoxy-2-methyl-3-indenylxtosyloxy acetate (0.01 mole) andmorpholine (0.03 mole) in 50 ml. 1,2-dimethoxyethane is heated underreflux for 4-8 hours under nitrogen. The mixture is concentrated toone-third volume, diluted with water and extracted with ether. Theethereal solution is washed with water and dried over sodium sulfate.Evaporation of the solution and chromatography of the residue on acolumn of 100 g. neutral alumina using ether-petroleum ether (v./v.50100%) as eluent gives the product,methyl-S-methoxy-2-methyl-3-indenyl-a-morpholino acetate.

The above product is then used in the procedure of Example 8 to give 1 pchlorobenzylidene 2 methyl- 5-methoxy-3-indenyl-a-morpholinoacetic acid.

EXAMPLE 38 u-[I-p-chlorobenzylidene-Z-methyl-5-methoxy-3- indenyl]-a-benzylthioacetic acid I-p-chlorobenzylidene-Z-methyl-S-methxy-3-indenyl-a-fluorometlzylacetic acid The procedure of Example 2 isfollowed using ethyl-abromo-B-fiuoropropionate in place of ethylbromoacetate to produce ethyl-Z-methyl--methoXy-3-indenyl-a-fluoromethylacetate. This is then used in the procedure of Example 8 to produce1-p-chlorobenzylidene-Z-methyl-S- methoxy-a-fluoromethylacetic acid.

22. EXAMPLE 40 I-p-chlorobenzy lidene-Z-flaorom ethyl-5-meth0xy-3-indenylacetic acid The procedure of Example 1 is followed, usingethyla-bromo-B-fluoropropionate in place of ethyl-2-bromopropionate togive 6-methoxy-Z-fluoromethylindanone. This is then used in theprocedure of Example 2 to give ethyl-Z-fluoromethyl-5-methoxy-3-indenylacetate which, when used in the procedure of Example 8, givesl-p-chlorobenzylidene 2 fluoromethyl 5 methoxy 3 indenylacetic acid.

EXAMPLE 41 a-(1-p-chlorobenzylidene-Z,6-dimethyl-3-indcnyl) glycine (A)Ethyl 2,6 dimethyl 3 indenyl a acetamido acetate.-The product of Example30A is stirred in pyridine with an excess of acetic anhydride. Themixture is drowned in water and the product, ethyl-2,6-dimethyl-3-indenyl-a-acetamido acetate, is extracted with ether. The extracts arewashed with dilute HCl and then to neutral with water. The extract isdried over Na SO and evaporated.

(B) 1 p chlorobenzylidcne 2,6 dimethyl 3 indenyl-a-acemmidoaceticacid.The product of Part A is used in the procedure of Example 8 toyield the abovenamed compound.

(C) a (1 p chlorobenzylia'ene 2,6 dimethyl 3- irzdenyl)glycine.-Theproduct of Part B is heated on a steam bath in 2N NaOH solution for sixhours. The mixture is cooled and neutralized to pH 6.5 with dilute HClto yield the above-named amino acid.

EXAMPLE 42 1-p-chlor0benzylidene-Z-methyl-5-methoxy-3-indenyl-a-alkylacetic acid (A) 1 pchlorobenzylidene-Z-methyl-5-m:eth0xy-3windenylacetamide.The procedureof Example 18 is followered using an ether solution of ammonia in placeof the morpholine, to yield the above amide.

(B) 1 p choro benzylidene-Z-methyZ-S-meth0xy-3-indenyl acet0nitrile.Amixture of 10 g. of the amide from Part A and 20 cc. of POCI is heatedat -100 for 4-5 hours.. The mixture is then poured into ice water andextracted with ml. of ether. The extract is washed with sodiumbicarbonate, dried over Na SO and evaporated, to yield the abovenitrile.

(C) 1 p chlorobenzylidene-Z-methyl-5-meth0xy-3-indenyl-a-allylacetonitrile.--Amixture of 0.01 mole of the nitrile from Part B and 0.01 mole of NaNH intoluene (100 cc.) is stirred at room temperature. Allyl chloride (0.015mole) is added'and the mixture is stirred for 3-4 hours. It is thenpoured into a large volume of Water and extracted with ether. Theextract is dried and evaporated to dryness, to yield the a-allylnitrile. V

(D) 1 p chlorobenzylidene-Z-methyl-5-miethoxy-3- indenyl-a-allylaceticacid.-The a-allyl nitrile from Example 430 is refluxed 8 hours in a[large volume of 6 N sulfuric acid. The mixture is then cooled, dilutedwith four to five volumes of water and extracted with ether.

. The extract is dried and evaporated to dryness to yield hours at roomtemperature and then two hours at reflux.

The mixture is drowned in a large volume of water and the benzene layeris separated and dried. Evaporation of the benzene leaves as a residueethyl-a-(2,6-dimethyl-3- indenyl) acrylic acid.

23 (B) or (I-p-chlorobenzylidene 2,6-dimethyl 3-indenyl)acrylicacid.-The product of Example 44A is used in the procedure of Example 8to produce a-(l-p-chlorobenzylidene-2,6-dimethyl-3-indenyl)acrylic acid.

EXAMPLE 44 is filtered, washed neutral with water and slurried in diluteaqueous sodium bicarbonate solution. This slurry is filtered and thefiltrate is acidified. The precipitate,1-pchlonobenzylidene-Z-methyl-5-amin0-3 indenylacetic acid, is isolatedby filtration, washed and dried.

(C) 1 p chlorobenzylidene-2-methyl-j-acetylamino- 3-indenylacetic acid.Amixture of 5 g. of the product of Part B, 5 g. of acetic anhydride and50 m1. of pyridine is heated to reflux until no substantial test forfree amine can be obtained on an aliquot. The mixture is then evaporatedto dryness in vacuo to y'eld l-p-chlorobenzylidene 2' methyl5-acetylamino-3-indenyl acetic acid. When other acid anhydrides such aspropionic anhydride, butyric anhydride, or acid chlorides such asbenzoylchloride are used in place of acetic anhydride, the correspondingS-acylamino compound is obtained.

(D) 1 p chlorobenzylidene-Z-methyl-S-methylamina- 3-indenylaceticacid.-A mixture of 0.1 mole of the product of Part C, 0.1 mole ofsodiumhydride and lOO ml. of dimethylformamide is stirred at room temperaturewhile 0.15 mole of methyliodide is added. The mixture is stirred untilthe reaction is substantially complete and then is added to 200 ml.ofcold water. After excess NaOH solution is added, the mixture isrefluxed until deacylation is substantially complete. Acidification ofthe mixture gives a precipitate of l-chlorobenzylidene-2-methyl-5-methylamino-3-indenylacetic acid.

(E) 1 p chlorobenzylidene 2-methyl-5-cyano-3-indenylacezic acid.--Theproduct of Example 45B is dissolved in twenty times its weight of 5 NHCl and slightly over one mole proportion of sodium nitrile is addedgradually at OS C. The mixture is then stirred until diazotization iscomplete. The mixture is then poured, with stirring, into a slurry ofcuprous cyanide in water containing excess sodium carbonate, thesolution being kept alkaline by the addition of more Na CO as needed.The mixture is then filtered and the filtrate is acidified. Theprecipitated product is filtered, dried and recrystallized frompetroleum ether and ether to givel-p-chlorobenzylidene-Z-methyl-5-cyano-3-indenylacetic acid.

(F) 1 p chlorobenzylidene-Z-methyl-5-carboxamid0- 3-indenyl-aceticacid.--The product of Part E is stirred at room temperature withconcentrated sulfuric acid until hydrolysis is substantially complete.The product is isolated by drowning in water. It is the above-namedcarboxamido compound.

(G) 1-p-chl0r0benzylidene-Z-methyl-5-carb0xy 3 indenyl acetic acid.-Theproduct of Part F is refluxed in 5 N NaOH until hydrolysis issubstantially complete. Acidification of-the mixture precipitates theabove named product. When this product is stirred at ambient temperaturein methanol, ethanol, propanol or butanol, in the presence of asmallamount of sulfuric acid, the corresponding methyl, ethyl, propyl orbutyl ester is formed, as e.g.,1-p-chlorobenzylidene-2-methy1-5-carbomethoxy- 3-indenyl-acetic acidmethyl ester. a

24 EXAMPLE 4s 1 -p-chloro-'benzylidene-2-methyl-5-methylthi0-3-indenylacetic acid The procedure of Example 1 is followed substituting pmethylthio benzaldehyde for p-anisaldehyde, to give ethyl-Z-hydroxy-Z-(pmethylthiophenyl) 1 methylpropionate and from this6-methylthio-2-methylindanone. This product is then used in theprocedure of Example 2 to give ethyl-5-methylthio 2 methyl 3indenylacetate, which, when used in the procedure of Example 8, gives1-p-chlorobenzylidene-2-methyl-5-methylthio-3 indenylacetic acid.

When, in the above procedure, 4-methyl-sulfonylbenzaldehyde, 4dimethylsulfamylbenzaldehyde, 4-dimethylaminoethylbenzaldehyde, 4phenylsulfonylbenzaldehyde, 4 benzyloxybenzaldehyde, 4phenoxybenzaldehyde or 4-cyclohexylbenzaldehyde .is used in place ofmethylthiobenzaldehyde, there is obtained the corresponding 5-methylsulfonyl, S-dimethylsulfamyl, 5 -dimethylaminoethyl,5-phenylsulfonyl, 5sbenzyloxy, S-phenoxy and 5- cyclohexyl indenecompounds.

When the S-methylthio compound prepared above is use-d in the procedureof Example 14, the corresponding S-mercapto compound is formed.

EXAMPLE 46 1-p-chlorobenzylidene-Z-methyl-5-allyl0xy-3-indenylaceticacid A mixture of 0.1 mole of l-p-ch-lorobenzylidene-Z-methyl-5-hydroxy-3-indenylacetic acid, 500' ml. of acetone, O.2 mole ofK CO and 0.15 mole of allyl chloride is refluxed overnight. The mixtureis then drowned in a large amount of water and after acidification,extracted with ether. The ether extract is dried and evaporated to yieldthe S-allyloxy compound.

When cyclopentylbromide is used in place of the allylbromide, thecorresponding S-cyclopentyloxy compound is obtained.

EXAMPLE 47 1-p-chl0r0'benzylidene-Z-m thyl-5 vinyl-3-indenylacetic acidA mixture ofl-p-chlorobenzylidene-2-methyl-5-dimethylaminoethyl-3-indenylacetic acid(Example 46), molar excess of methyliodide and ethanol is heated untilquaternization is complete. Evaporation to dryness in vacuo yields theresidue consisting of the S-trimethyla-mmonium ethyl iodide salt. Thissalt is then dissolved in 2 N NaOH and the mixture is heated four hourson a steam bath. The mixture is then cooled and acidified. Theprecipitated l-chlorobenzylidene-2-methyl-5-vinyl 3 indenylacetic acidis filtered and dried.

We claim:

1. A compound of the structure:

in which R is aryl or heterocyclic aromatic radical;

R is alkyl, phenyl lower alkyl, phenyl, thienyl halogen, hydroxy,alkoxy, haloalky-l, alkylthio and phenylthio;

R is hydrogen, lower alkyl, haloloweralkyl, fluorine,

amino, acylamino, N-morpholino, dialkylamino, alkenyl, aralkylthio,hydroxy, alkoxy and together with R' a methylene;

R' is hydrogen or together with R a methylene;

R is alkyl, alkoxy, nitro, amino, acylamino, a-lkylamino, dialky-lamino,dialkylaminoalkyl, sulfamyl,

1. A COMPOUND OF THE STRUCTURE: